PROJECT SUMMARY Of more than 3.5 million breast cancer survivors in the U.S. today, an estimated one-third have undergone mastectomy. Of these 1.2 million survivors, 40% have had or are considering breast reconstruction procedures. In 2018, an additional 250,000 adult women will receive a breast cancer diagnosis and an estimated 100,000 will undergo mastectomy. Advances in breast reconstruction techniques for women with mastectomy have contributed to improved patient and partner satisfaction by restoring aesthetic aspects or form of the breast. However, even the most advanced reconstructive techniques do not preserve breast function. Loss of breast sensation after mastectomy is a prevalent, well-established and distressing outcome for women that is rarely addressed in the course of breast cancer care. Failure to restore breast function may explain high rates of sexual dysfunction (37-77%) in breast cancer survivors, even among women satisfied with the aesthetic outcome. Little is known about the neural basis of sensory function in the intact breast or about the interactions between sexual arousal and breast sensation. To fill the gap, we will develop and validate a comprehensive patient-reported measure of breast sensory function for use in women with and without breast cancer. We will administer this measure together with the PROMIS Sexual Function and Satisfaction measure to a sample of 500 women with and without breast cancer to examine the relationship between breast sensory function and sexual function following treatment for breast cancer. In parallel, we will apply state-of-the-art psychophysical sensory assays to determine the relative contributions of nerve fibers toward various aspects of breast sensation, as we and others have successfully done in the glabrous skin of the hand. In addition, we will assess the modulation of breast sensation as well as the sensory consequences of blocking individual nerves known to innervate the breast. These experiments on healthy subjects will provide a detailed characterization of breast sensory function, its neural basis, and its modulation by arousal. The specific aims of this research are to: (1) Develop and validate a self-report measure of breast sensory function and examine the link between breast sensory function and sexual function in affected and unaffected women and, (2) Characterize breast sensation, examine its modulation by arousal, and establish its neural substrates using state-of-the-art psychophysical techniques. Together, these aims will improve our understanding of breast sensory function and its relationship to sexual function, permit us to estimate the impact of sensory loss on sexual function and satisfaction, and provide a means to identify women at greatest risk of sexual dysfunction following mastectomy. This developmental work will lay the foundation for surgical innovation and/or the development of a bionic breast to preserve or restore breast function following mastectomy. This proposal addresses NCI?s research priority to alleviate the adverse effects of cancer and its treatment.